US11752149B2 - Muscarinic acetylcholine M1 receptor antagonists - Google Patents
Muscarinic acetylcholine M1 receptor antagonists Download PDFInfo
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- US11752149B2 US11752149B2 US17/103,455 US202017103455A US11752149B2 US 11752149 B2 US11752149 B2 US 11752149B2 US 202017103455 A US202017103455 A US 202017103455A US 11752149 B2 US11752149 B2 US 11752149B2
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- pharmaceutically acceptable
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- alkyl
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- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- PSACHCMMPFMFAJ-UHFFFAOYSA-N nmm n-methylmorpholine Chemical compound CN1CCOCC1.CN1CCOCC1 PSACHCMMPFMFAJ-UHFFFAOYSA-N 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 238000013546 non-drug therapy Methods 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Chemical group C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Chemical group 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Chemical group 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 230000037152 sensory function Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- PSDAEKDIOQXLLC-DTORHVGOSA-N tert-butyl (1r,5s)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@@]2([H])CC[C@]1([H])N2 PSDAEKDIOQXLLC-DTORHVGOSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- IKVDXUFZJARKPF-UHFFFAOYSA-M zinc;cyclopropane;bromide Chemical compound Br[Zn+].C1C[CH-]1 IKVDXUFZJARKPF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the human muscarinic acetylcholine receptor M 1 (mAChR M 1 ) is a protein of 479 amino acids encoded by the CHRM1 gene.
- the mAChR M 1 is one of five members of the family of muscarinic acetylcholine receptors (M 1 -M 5 ), which are widely expressed throughout the body where they have varying roles in cognitive, sensory, motor, and autonomic functions.
- the M 1 mAChR is found in both the central and peripheral nervous systems, particularly in the cerebral cortex and sympathetic ganglia.
- highly selective mAChR M 1 antagonists may have potential utility in the treatment of some epileptic disorders, as well as certain movement disorders, including Parkinson's disease, dystonia, and fragile X syndrome.
- This disclosure provides, for example, compounds and compositions which are antagonists of the muscarinic acetylcholine M 1 receptor (mAChR M 1 ), and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active ingredient.
- the disclosure also provides for the use of disclosed compounds as medicaments and/or in the manufacture of medicaments for the inhibition of muscarinic acetylcholine M1 receptor activity in patients.
- Y is —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 2 is independently selected from hydrogen, deuterium, or C 1-6 alkyl;
- R 3 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- Y is —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- R 1 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- each R 4 is independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, or C 1-6 alkylhydroxyl.
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl.
- n is 2.
- n is 1.
- composition comprising a compound of Formula (IA), (IB), (IIA), (IIB), or (III), a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
- a method of treating a neurodegenerative disorder in a subject in need thereof comprising administering to subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating neuropathy in a subject in need thereof comprising administering to subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy.
- a method of treating neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy.
- a method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system.
- a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis.
- a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.
- the method further comprises the administration of one or more immunomodulatory agents.
- the one or more immunomodulatory agents are selected from: an IFN- ⁇ 1 molecule, or the like; a corticosteroid, or the like; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer, or the like; an antibody or fragment thereof against alpha-4 integrin or natalizumab, or the like; an anthracenedione molecule or mitoxantrone, or the like; a S1P1 functional modulator or fingolimod, or the like; a NRF2 functional modulator or dimethyl fumarate, or the like; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab, or the like; an antibody against CD52 or alemtuzumab, or the like; an antibody against CD20 or ocrelizumab, or the like
- a method of modulating muscarinic acetylcholine receptor M 1 activity in a subject comprising administering to the subject a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- the compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof acts as a selective M 1 antagonist.
- This disclosure is directed, at least in part, to compounds capable of inhibiting the muscarinic acetylcholine M 1 receptor.
- C 1 -C x includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
- C 1 -C x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
- C 1-x includes C 1-2 , C 1-3 . . . C 1-x .
- C 1-x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
- Amino refers to the —NH 2 radical.
- Haldroxyl refers to the —OH radical.
- Niro refers to the —NO 2 radical.
- Oxa refers to the —O— radical.
- Oxo refers to the ⁇ O radical.
- Thioxo refers to the ⁇ S radical.
- Oximo refers to the ⁇ N—OH radical.
- Alkyl or “alkylene” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl or C 1-15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl or C 1-13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl or C 1-8 alkyl).
- an alkyl comprises one to six carbon atoms (e.g., C 1 -C 6 alkyl or C 1-6 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl or C 1-5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl or C 1-4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl or C 1-3 alkyl).
- an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl or C 1-2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl or C 5-15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl or C 5-8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl or C 2-5 alkyl).
- an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl or C 3-5 alkyl).
- the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl).
- the alkyl is attached to the rest of the molecule by a single bond.
- an alkyl group is optionally substituted by one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, —OR a , —SR a , —OC(O)R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR f , —OC(O)—NR a R f , —N(R a )C(O)R f , —N(R a )S(O) t R f (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R f (where t is 1 or 2), —S
- Alkoxy refers to a radical bonded through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.
- Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
- an alkenyl group is optionally substituted by one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, —OR a , —SR a , —OC(O)—R f , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR f , —OC(O)—NR a R f , —N(R a )C(O)R f , —N(R a )S(O) t R f (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R f (where t is 1 or 2),
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
- an alkynyl group is optionally substituted by one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, —OR a , —SR a , —OC(O)R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR f , —OC(O)—NR a R f , —N(R a )C(O)R f , —N(R a )S(O) t R f (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R f (where t is 1 or 2),
- Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
- the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
- the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
- aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O
- Aryloxy refers to a radical bonded through an oxygen atom of the formula —O-aryl, where aryl is as defined above.
- Alkyl refers to a radical of the formula —R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- Alkyloxy refers to a radical bonded through an oxygen atom of the formula —O-aralkyl, where aralkyl is as defined above.
- Alkenyl refers to a radical of the formula —R d -aryl where R d is an alkenylene chain as defined above.
- the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
- the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
- Alkynyl refers to a radical of the formula —R e -aryl, where R e is an alkynylene chain as defined above.
- the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
- the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
- Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged or spirocyclic ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond.
- Cycloalkyls are saturated, (i.e., containing single C—C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.)
- monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- a cycloalkyl comprises three to eight carbon atoms (e.g., C 3 -C 8 cycloalkyl or C 3-8 cycloalkyl).
- a cycloalkyl comprises three to seven carbon atoms (e.g., C 3 -C 7 cycloalkyl or C 3-7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C 3 -C 6 cycloalkyl or C 3-6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C 3 -C 5 cycloalkyl or C 3-5 cycloalkyl).
- a cycloalkyl comprises three to four carbon atoms (e.g., C 3 -C 4 cycloalkyl or C 3-4 cycloalkyl).
- a partially unsaturated cycloalkyl is also referred to as “cycloalkenyl.”
- monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[4.4]nonanyl, and the like.
- cycloalkyl is meant to include cycloalkyl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a ) 2 , —R b —C(O)OR
- Cycloalkoxy refers to a radical bonded through an oxygen atom of the formula —O— cycloalkyl, where cycloalkyl is as defined above.
- Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above.
- Haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halogen radicals, as defined above.
- Halocycloalkyl refers to a cycloalkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above.
- Halocycloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halogen radicals, as defined above.
- Alkylhydroxyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above.
- Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated.
- the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s).
- heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl
- heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)R a , —R b —
- Heteroaryl refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
- the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
- Heteroaryl includes fused or bridged ring systems.
- the heteroatom(s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —OR a , —R b —OC(O)—N(R a ) 2 , —R b —OR a , —R b —OC(O)—N(R
- N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
- An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
- a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- Heteroaryloxy refers to radical bonded through an oxygen atom of the formula —O-heteroaryl, where heteroaryl is as defined above.
- Heteroarylalkyl refers to a radical of the formula —R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
- Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
- Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
- optionally substituted aryl means that the aryl radical is or is not substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
- the compounds presented herein exist as tautomers.
- a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
- Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
- salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997).
- Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dib enzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge e
- “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient.
- Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
- Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.
- Prodrug is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein.
- prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
- a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, for example, Bundgard, H., Design of Prodrugs , Amsterdam: Elsevier, 1985). Discussions of prodrugs can also be found in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series , Vol. 14, and in Roche, E. B., ed. Bioreversible Carriers in Drug Design , Oxford: Pergamon Press, 1987.
- prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of an active compound, as described herein can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
- Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
- Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol in the active compounds and the like.
- solvates refers to a composition of matter that is the solvent addition form.
- solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like.
- “Hydrates” are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
- allosteric site and “allosteric binding site” refer to a ligand binding site that is topographically distinct from the orthosteric binding site.
- orthosteric site and “orthosteric binding site” refer to the primary binding site on a receptor that is recognized by an endogenous ligand or agonist for the receptor.
- the orthosteric site on the muscarinic acetylcholine M 1 receptor is the site that acetylcholine binds.
- ligand refers to a natural or synthetic molecule that is capable of binding to or associating with a receptor to form a complex and mediate, prevent, or modify a biological effect.
- ligand is meant to encompass allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogs of natural substrates.
- natural ligand and “endogenous ligand” refer to a naturally occurring ligand which binds to a receptor.
- mAChR M 1 receptor antagonist refers to any exogenously administered compound or agent that is capable of partially or completely inhibiting, or reversing, the effect of an agonist (e.g. acetylcholine) on the mAChR M 1 receptor.
- the term is inclusive of compounds or agents characterized or described as antagonists, partial antagonists, and negative allosteric modulators.
- mAChR M 1 receptor antagonists can mediate their effects by binding to the orthosteric site or to allosteric sites, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity.
- a mAChR M 1 receptor antagonist directly or indirectly inhibits the activity of the mAChR M 1 receptor in the presence or in the absence of acetylcholine, or another agonist, in an animal, in particular a mammal, for example a human.
- a mAChR M 1 receptor antagonist decreases the activity of the mAChR M 1 receptor in a cell in the presence of extracellular acetylcholine.
- a compound that is a “mAChR M 1 receptor antagonist” includes a compound that is a “mAChR M 1 receptor competitive antagonist,” a “mAChR M 1 receptor noncompetitive antagonist,” a “mAChR M 1 receptor partial antagonist,” or a “mAChR M 1 receptor negative allosteric modulator.”
- mAChR M 1 receptor competitive antagonist refers to any exogenously administered compound or agent that is capable of binding to the orthosteric site of mAChR M 1 receptors without activating the receptor.
- a competitive antagonist can interact with a mAChR M 1 receptor and compete with the endogenous ligand, acetylcholine, for binding to the receptor and decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
- mAChR M 1 receptor noncompetitive antagonist refers to any exogenously administered compound or agent that binds to site that is not the orthosteric binding site of mAChR M 1 receptors, and is capable of partially or completely inhibiting, or reversing, the effect of an agonist (e.g., acetylcholine) on the mAChR M 1 receptor.
- a non-competitive antagonist can interact with a mAChR M 1 receptor and decrease the binding of the endogenous ligand, acetylcholine, to the receptor and/or decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
- mAChR M 1 partial antagonist refers to any exogenously administered compound or agent that can bind to an orthosteric or an allosteric site, but the effect of binding is to only partially block effect of mAChR M 1 receptor response to an agonist, e.g., acetylcholine.
- a partial antagonist can interact with a mAChR M 1 receptor and but is not capable of fully inhibiting the response of the mAChR M 1 receptor to an agonist, e.g., acetylcholine.
- mAChR M 1 negative allosteric modulator refers to any exogenously administered compound or agent that binds an allosteric site that directly or indirectly inhibits the activity of the mAChR M 1 receptor in the presence of acetylcholine, or another agonist, in an animal, in particular a mammal, for example a human.
- a selective muscarinic M 1 negative allosteric modulator can preferentially bind to the muscarinic M 1 receptor and decrease muscarinic M 1 signaling by acting as a non-competitive antagonist.
- a mAChR M 1 receptor negative allosteric modulator decreases the activity of the mAChR M 1 receptor in a cell in the presence of extracellular acetylcholine.
- “selective” or “selectivity” or the like in reference to a compound or agent refers to the compound's or agent's ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward muscarinic acetylcholine M 1 receptor (mAChR M 1 ) would preferentially inhibit mAChR M 1 over other muscarinic receptors).
- a particular molecular target e.g., protein, enzyme, etc.
- mAChR M 1 a compound having selectivity toward muscarinic acetylcholine M 1 receptor
- a “muscarinic acetylcholine M 1 receptor selective compound” or “mAChR M 1 -selective compound” refers to a compound (e.g., compounds described herein) having selectivity towards muscarinic acetylcholine M 1 receptor (mAChR M 1 ).
- the compound e.g., compound described herein
- the compound is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold more selective for muscarinic acetylcholine M 1 receptor (mAChR M 1 ) over one or more of the mAChR M 2 , M 3 , M 4 , or M 5 receptors.
- the compound e.g., compound described herein
- the compound is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100-fold more selective for muscarinic acetylcholine M 1 receptor (mAChR M 1 ) over one or more of the mAChR M 2 , M 3 , M 4 , or M 5 receptors.
- mAChR M 1 muscarinic acetylcholine M 1 receptor
- subject or “patient” encompasses mammals.
- mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
- the subject is a human.
- treatment or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit.
- therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
- a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
- the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
- EC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
- EC 50 can refer to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay.
- in vitro assay systems utilize a cell line that either expresses endogenously a target of interest or has been transfected with a suitable expression vector that directs expression of a recombinant form of the target.
- IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
- IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
- an IC 50 for mAChR M 1 receptor can be determined in an in vitro assay system.
- This disclosure provides compounds which are antagonists of the muscarinic acetylcholine M 1 receptor (mAChR M 1 ). These compounds, and compositions comprising these compounds, are useful for the treatment or prevention of neurological disorders. In some embodiments, the compounds described herein are useful for treating multiple sclerosis.
- mAChR M 1 muscarinic acetylcholine M 1 receptor
- Y is a —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 2 is independently selected from hydrogen, deuterium, or C 1-6 alkyl;
- R 3 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- Y is a —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- R 1 is
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 6 is selected from halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 6 is selected from fluorine, cyano, methyl, or trifluoromethyl.
- p is 0 to 1, 0 to 2, 1 to 2, 1 to 3, or 2 to 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.
- R 3 is
- R 6 is selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy.
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 3 is
- R 6 is selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy. In some embodiments, R 6
- R 3 is
- R 6 is selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy.
- R 3 is
- R 3 is
- the compound is useful as a comparator compound.
- the comparator compound can be used to assess the activity of a test compound in an assay (e.g., an assay as described herein, for example in the examples section, FIGURES, or tables).
- the compound is a compound described herein (e.g., in the Compounds section, Examples Section, Methods Section, or in a claim, table, or FIGURE).
- the compounds described herein include all possible tautomers within the formulas described herein. Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
- Z isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
- the compounds described herein possess one or more chiral centers and each center exists in the (R)-configuration, or (S)-configuration.
- the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
- mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
- the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
- the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
- dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
- the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
- the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
- geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
- positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
- the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
- the compound is deuterated in at least one position.
- deuterated forms can be made by the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997.
- deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
- structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
- the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
- the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
- isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
- Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure
- the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
- the methods of synthesis for deuterium-containing compounds are known in the art.
- deuterium substituted compounds are synthesized using various methods such as described in: Dean, D. C.; “Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development,” Curr. Pharm. Des., 2000, 6(10); George W.; Varma, R. S., “The Synthesis of Radiolabeled Compounds via Organometallic Intermediates,” Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. A., “Synthesis of radiolabeled compounds,” J. Radioanal. Chem., 1981, 64(1-2), 9-32.
- the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- the compounds described herein exist as their pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
- the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
- the compounds described herein exist as solvates.
- the present disclosure provides for methods of treating diseases by administering such solvates.
- the present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
- the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- the compounds described herein exist in prodrug form.
- the present disclosure provides for methods of treating diseases by administering such prodrugs.
- the disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
- prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present disclosure.
- the amino acid residues include but are not limited to the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
- prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure.
- prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
- compounds having free amino, amido, hydroxy or carboxylic groups are converted into prodrugs.
- free carboxyl groups are derivatized as amides or alkyl esters.
- all of these prodrug moieties incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
- Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulfide containing esters; ethers, amides, carbamates, hemi succinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in Fleisher, D. et al., “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs,” Advanced Drug Delivery Reviews, 1996, 19, 115-130.
- esters such as though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters
- Amine derived prodrugs include, but are not limited to the following groups and combinations of groups:
- the compound of Formula (IA), (IB), (IIA), (IIB), or (III) as described herein is administered as a pure chemical.
- the compound of Formula (IA), (IB), (IIA), (IIB), or (III) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Gennaro, A. R., “Remington: The Science and Practice of Pharmacy,” 21 st ed., Easton: Lippincott Williams & Wilkins, 2005.
- a pharmaceutical composition comprising at least one compound of Formula (IA), (IB), (IIA), (IIB), or (III) described herein, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers.
- the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IA), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IB), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IIA), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IIB), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
- the compound of Formula (IA), (IB), (IIA), (IIB), or (III) as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
- compositions include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ophthalmic, or aerosol administration.
- parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
- vaginal e.g., vaginal, ophthalmic, or aerosol administration.
- Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
- the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
- the active compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
- the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof.
- a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
- a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalc
- the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding
- fillers or extenders such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose
- compositions comprise buffering agents.
- solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet is made by compression or molding, optionally with one or more accessory ingredients.
- compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
- tablets, and other solid dosage forms, such as dragees, capsules, pills and granules are scored or prepared with coatings and shells, such as enteric coatings and other coatings.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
- inert diluents such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl be
- suspensions in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
- suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
- Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active component is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as required.
- the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- the compounds described herein are formulated as eye drops for ophthalmic administration.
- compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
- a non-aqueous (e.g., fluorocarbon propellant) suspension is used.
- sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions.
- an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
- the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (e.g., Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
- compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
- polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate and cyclodextrins.
- Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
- Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
- the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
- the pH of the duodenum is about 5.5
- the pH of the jejunum is about 6.5
- the pH of the distal ileum is about 7.5.
- enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
- Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins
- the dose of the composition comprising at least one compound of Formula (IA), (IB), (IIA), (IIB), or (III) as described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.
- patient's e.g., human
- compositions are administered in a manner appropriate to the disease to be treated (or prevented).
- An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
- an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
- Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
- Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
- Disclosed compounds are administered to subjects or patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors, with the appropriate dosage ultimately being at the discretion of the attendant physician.
- a contemplated compound disclosed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
- the muscarinic acetylcholine receptor M 1 (mAChR M 1 ) is found in both the central and peripheral nervous systems, particularly in the cerebral cortex and sympathetic ganglia. Notably, M 1 is expressed on oligodendrocyte precursor cells (OPCs) in the central nervous system. Over time, OPCs will differentiate into myelin-producing oligodendrocytes. Myelin is indispensable for action potential conduction along the axon and its loss has been attributed to neurodegenerative disorders, specifically multiple sclerosis. In some embodiments, selective mAChR M 1 antagonists accelerate OPC differentiation into oligodendrocytes.
- OPCs oligodendrocyte precursor cells
- selective mAChR M 1 antagonists are useful in the treatment of demyelinating disorders, such as multiple sclerosis. In some embodiments, selective mAChR M 1 antagonists are useful in treating epileptic disorders and certain movement disorders, including Parkinson's disease, dystonia, and fragile X syndrome.
- the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M 1 receptor (mAChR M 1 ). In some embodiments, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M 1 receptor (mAChR M 1 ) over one or more of the mAChR M 2 , M 3 , M 4 , or M 5 receptors. In some embodiments, a compound disclosed herein exhibits an IC 50 for the mAChR M 1 response which is about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, or >100-fold less than that for mAChR M 2 .
- a compound disclosed herein exhibits an IC 50 for the mAChR M 1 response which is about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, or >100-fold less than that for mAChR M 3 . In some embodiments, a compound disclosed herein exhibits an IC 50 for the mAChR M 1 response which is about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, or >100-fold less than that for mAChR M 4 .
- a compound disclosed herein exhibits an IC 50 for the mAChR M 1 response which is about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, or >100-fold less than that for mAChR M 5 .
- a compound disclosed herein exhibits an IC 50 for the mAChR M 1 response which is about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, or >100-fold less than that for mAChR M 2 , M 3 , M 4 , or M 5 , or combinations thereof.
- the compounds disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders wherein the patient or subject would benefit from antagonism of the muscarinic acetylcholine M 1 receptor.
- a treatment can include selective M 1 receptor antagonism to an extent effective to affect cholinergic activity.
- disorders for which the compounds disclosed herein are useful can be associated with cholinergic activity, for example cholinergic hyperfunction.
- a method of treating or preventing a disorder in a subject comprising the step of administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein in a dosage and amount effective to treat the disorder in the subject.
- a method for the treatment of one or more disorders, for which muscarinic acetylcholine receptor inhibition is predicted to be beneficial in a subject comprising the step of administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein in a dosage and amount effective to treat the disorder in the subject.
- a method of treating a neurodegenerative disorder in a subject in need thereof comprising administering to subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy.
- a method of treating neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy.
- a method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system.
- a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis.
- a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.
- a method of modulating muscarinic acetylcholine receptor M 1 activity in a subject comprising administering to the subject a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.
- the compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof acts as a selective M 1 antagonist.
- combination therapies for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
- a compound described herein is administered in combination with one or more immunomodulatory agents.
- a compound described herein is administered in combination with one or more immunomodulatory agents, wherein the immunomodulatory agents are selected from an IFN- ⁇ 1 molecule; a corticosteroid; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthracenedione molecule or mitoxantrone; a fingolimod or other S1Pl functional modulator; a dimethyl fumarate or other NRF2 functional modulator; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ocrelizumab; and an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
- the immunomodulatory agents are selected from an IFN- ⁇ 1 molecule; a cortico
- the immunomodulatory agent is an IFN- ⁇ 1 molecule. In some embodiments, the immunomodulatory agent is a corticosteroid. In some embodiments, the immunomodulatory agent is a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer. In some embodiments, the immunomodulatory agent is an antibody or fragment thereof against alpha-4 integrin or natalizumab. In some embodiments, the immunomodulatory agent is an anthracenedione molecule or mitoxantrone. In some embodiments, the immunomodulatory agent is a fingolimod or other S1Pl functional modulator.
- the immunomodulatory agent is a dimethyl fumarate or other NRF2 functional modulator.
- the immunomodulatory agent is an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab.
- the immunomodulatory agent is an antibody against CD52 or alemtuzumab.
- the immunomodulatory agent is an antibody against CD20 or ocrelizumab.
- the immunomodulatory agent is an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
- the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
- Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected).
- Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
- Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents.
- Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
- the therapeutic agents are administered by the same route or by different routes.
- a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally.
- all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.
- Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies.
- the combination therapy further comprises a non-drug treatment
- the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
- the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
- the components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, that are administered either simultaneously or sequentially.
- Embodiment P1 A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IA) or (IB):
- Y is —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 2 is independently selected from hydrogen, deuterium, or C 1-6 alkyl;
- R 3 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- Embodiment P2 The compound of embodiment P1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIA) or (IIB):
- Y is —CH 2 —, —CH 2 CH 2 —, or —CH 2 OCH 2 —;
- R 1 is
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- Embodiment P3 The compound of embodiment P1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):
- each R 4 is independently selected from hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, or heterocycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each R 6 is independently selected from halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkoxy;
- n
- Embodiment P4 The compound of any one of embodiments P1-P3, or a pharmaceutically acceptable salt thereof, wherein R 1 is
- Embodiment P5 The compound of embodiment P4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
- Embodiment P6 The compound of any one of embodiments P1-P3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
- Embodiment P7 The compound of embodiment P6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
- Embodiment P8 The compound of any one of embodiments P1-P3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
- Embodiment P9 The compound of embodiment P8 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
- Embodiment P10 The compound of any one of embodiments P1-P9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
- Embodiment P11 The compound of embodiment P10, wherein R 3 is
- Embodiment P12 The compound of any one of embodiments P1-P9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
- Embodiment P13 The compound of embodiment P12, or a a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
- Embodiment P14 The compound of embodiment P13, wherein embodiments, R 3 is
- Embodiment P15 The compound of any one of embodiments P1-P9, or a a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
- Embodiment P16 The compound of embodiment P15, wherein embodiments, R 3 is
- Embodiment P17 The compound of any one of embodiments P1-P16, wherein n is 1.
- Embodiment P18 The compound of any one of embodiments P1-P16, wherein n is 2.
- Embodiment P19 A compound selected from:
- Embodiment P20 A pharmaceutical composition comprising a compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
- Embodiment P21 A method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt or solvate thereof.
- Embodiment P22 A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt or solvate thereof.
- Embodiment P23 The method of embodiment P22, wherein the demyelinating disease is a demyelinating disease of the central nervous system.
- Embodiment P24 The method of embodiment P23, wherein the disease is multiple sclerosis.
- Embodiment P25 The method of embodiment P22, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.
- Embodiment P26 A method of treating a neuropathic disease, optionally a peripheral neuropathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt or solvate thereof.
- Embodiment P27 The method of embodiment P26, wherein the neuropathic disease disease is diabetic neuropathy.
- Embodiment P28 The method of any one of embodiments P21-P27, further comprising the administration of one or more immunomodulatory agents.
- Embodiment P29 The method of embodiment P28, wherein the one or more immunomodulatory agents are selected from: an IFN- ⁇ 1 molecule; a corticosteroid; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthracenedione molecule or mitoxantrone; a fingolimod or FTY720 or other S1P1 functional modulator; a dimethyl fumarate or other NRF2 functional modulator; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ocrelizumab; and an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
- the one or more immunomodulatory agents are selected from: an IFN- ⁇ 1 molecule
- Embodiment P30 A method of modulating muscarinic acetylcholine receptor M 1 activity in a subject comprising administering to the subject a compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt or solvate thereof.
- Embodiment P31 The method of embodiment P30, wherein the compound acts as a selective M1 antagonist.
- the compounds used in the reactions described herein are made according to known organic synthesis techniques, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Ill.), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Combi-blocks (San Diego, Calif.), Crescent Chemical Co.
- Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry,” New York: John Wiley & Sons, Inc., 1982; Sandler S. R. et al., “Organic Functional Group Preparations,” 2 nd ed., New York: Academic Press, 1983; House, H. O., “Modern Synthetic Reactions,” 2 nd ed., Menlo Park: W. A. Benjamin, Inc., 1972; Gilchrist, T.
- Compounds of Formula (IA) or (IB) of the present disclosure may be prepared, for example, from a carboxylic acid (2) and amine (1a) or (1b), or its corresponding salt, in the presence of an appropriate coupling reagent such as HATU, EDC, T3P, or the like, and an appropriate base such as TEA, DIEA, or the like (Scheme 1).
- an appropriate coupling reagent such as HATU, EDC, T3P, or the like
- an appropriate base such as TEA, DIEA, or the like
- Step 1 In a dried round-bottom flask equipped with a magnetic stirrer and a reflux condenser was dissolved tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1 equiv) and 5-cyano-2-fluoropyridine (1.2 equiv) in acetonitrile (0.45 M). To this was then added potassium carbonate (2 equiv) in one rapid portion and the resulting suspension was stirred at reflux for 3 h. The reaction suspension was then cooled to RT and filtered. The insoluble was rinsed further with acetonitrile and the filtrate was concentrated in vacuo. The resulting residue was then partitioned between EtOAc and water.
- Step 2 In a dried round-bottom flask equipped with a magnetic stirrer was dissolved tert-butyl 8-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1 equiv) from the previous step in dichloromethane (0.42 M). To this was then added at 0° C. HCl (4 equiv, 4 M solution in dioxane, Sigma-Aldrich) in three portions over a period of 30 min. The resulting suspension was stirred at 0° C. for 1 h and then allowed to warm slowly to RT over 16 h.
- Step 1 In a sealable reaction tube purged and maintained with an inert atmosphere of nitrogen, was combined 1,2-diiodobenzene (2 equiv), methyl 4-sulfanylbutanoate (1 equiv), Pd 2 (dba) 3 CHCl 3 (0.1 equiv), XantPhos (0.2 equiv), and DIEA (2 equiv) in dioxane (0.32 M). The resulting solution was stirred for 12 h at 95° C. in an oil bath. The solids were filtered out and the filtrate was concentrated in vacuo.
- Step 1 In a 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was combined 4-bromo-1-fluoro-2-methoxybenzene (1 equiv), methyl 3-mercaptopropionate (2 equiv), Pd 2 (dba) 3 (0.1 equiv), Xantphos (0.2 equiv), and DIEA (2 equiv) in dioxane (0.65 M). The resulting solution was stirred for 2 h at 110° C. The solids were filtered out and the filtrate was concentrated in vacuo.
- Step 2 In a round-bottom flask was dissolved methyl 3-[(4-fluoro-3-methoxyphenyl)sulfanyl]propanoate (1 equiv) in MeOH (0.082 M). To this solution was then added an aqueous solution (0.32 M) of Oxone (2 equiv) dropwise at 0° C. over a period of 5 min. The resulting solution was stirred for 1 h at 25° C. and extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (lx), saturated aqueous NaHSO 3 (2 ⁇ ) and brine.
- Step 3 In a round-bottom flask was combined methyl 3-(4-fluoro-3-methoxybenzenesulfonyl)propanoate (1 equiv) and TFA (25 equiv) in H 2 O (0.52 M). The resulting solution was stirred for 2.5 h at 100° C. The resulting mixture was concentrated in vacuo to afford 3-(4-fluoro-3-methoxybenzenesulfonyl)propanoic acid as a yellow solid (>99% yield).
- LCMS: m/z 263 [M+H] + .
- Step 1 In a sealable reaction tube purged and maintained with an inert atmosphere of nitrogen was combined 1-bromo-3-fluoro-2-iodobenzene (1 equiv), bromo(cyclopropyl)zinc (2 equiv), and Pd(PPh 3 ) 4 (0.05 equiv) in THF (0.33 M). The resulting solution was stirred for 16 h at 60° C. in an oil bath before it was extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo and the resulting residue was applied onto a silica gel column.
- Step 2 In a sealable reaction tube purged and maintained with an inert atmosphere of nitrogen was combined 1-bromo-2-cyclopropyl-3-fluorobenzene (1 equiv), methyl 3-mercaptopropionate (1.2 equiv), Pd 2 (dba) 3 (0.1 equiv), Xantphos (0.2 equiv), and DIEA (3 equiv) in dioxane (0.28 M). The resulting solution was stirred for 2 h at 110° C. in an oil bath. The solids were filtered out and the filtrate was concentrated in vacuo.
- Step 3 In a round-bottom flask was combined methyl 3-[(2-cyclopropyl-3-fluorophenyl)sulfanyl]propanoate (1 equiv) and Oxone (2 equiv) in a 1:1 (v/v) solution of MeOH and H 2 O (0.072 M). The resulting solution was stirred for 1 h at 25° C. and extracted with dichloromethane. The combined organic extracts were concentrated in vacuo and the resulting residue was applied onto a silica gel column.
- Step 2 In a sealable reaction tube purged and maintained with an inert atmosphere of nitrogen was combined 1-bromo-2-(2,2-difluorocyclopropyl)benzene (1 equiv), methyl 3-mercaptopropionate (1.2 equiv), Pd 2 (dba) 3 (0.1 equiv), Xantphos (0.2 equiv), and DIEA (2 equiv) in dioxane (0.26 M). The resulting solution was stirred for 2 h at 110° C. in an oil bath. The solids were filtered out and the filtrate was concentrated in vacuo.
- Step 3 In a round-bottom flask was combined methyl 3-[[2-(2,2-difluorocyclopropyl)-phenyl]sulfanyl]propanoate (1 equiv) and Oxone (2 equiv) in a 1:1 (v/v) solution of MeOH and H 2 O (0.11 M). The resulting solution was stirred for 2 h at 25° C. and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo and the resulting residue was purified by Flash-Prep-HPLC to afford methyl 3-((2-(2,2-difluorocyclopropyl)phenyl)sulfonyl)propanoate as a yellow oil.
- Step 1 In a round-bottom flask was dissolved 1-(5-bromo-2-fluorophenyl)ethanone (1 equiv) in THF (0.58 M). To this solution was then added MeLi (2 equiv, 1.6 M solution in diethyl ether) dropwise over 5 min at ⁇ 78° C. The resulting mixture was stirred for 1 h at ⁇ 78° C. followed by 1 h at 0° C. under a nitrogen atmosphere. The reaction was quenched with water at 0° C. and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , filtered and the filtrate concentrated in vacuo.
- Step 2 In a sealable reaction vial purged and maintained with an inert atmosphere of nitrogen was combined 2-(5-bromo-2-fluorophenyl)propan-2-ol (1 equiv), methyl 3-mercaptopropionate (2 equiv), Pd 2 (dba) 3 CHCl 3 (0.1 equiv), Xantphos (0.2 equiv), and DIEA (2 equiv) in dioxane (0.38 M). The resulting solution was stirred for 2 h at 100° C. The solids were filtered out and the filtrate was concentrated in vacuo.
- Step 3 In a round-bottom flask was dissolved methyl 3-[[4-fluoro-3-(2-hydroxypropan-2-yl)phenyl]sulfanyl]propanoate (1 equiv) in MeOH (0.37 M). To this solution was then added an aqueous solution (0.73 M) of Oxone (2 equiv) dropwise at 0° C. over a period of 5 min. The resulting mixture was stirred for 4 h at 25° C. and then extracted with CH 2 Cl 2 . The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , filtered and the filtrate concentrated in vacuo.
- Example 35 and 36 Synthesis of 6-(3-(3-((2-((R)-2,2-difluorocyclopropyl)phenyl)-sulfonyl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)nicotinonitrile and 6-(3-(3-((2-((S)-2,2-difluorocyclopropyl)phenyl)sulfonyl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)nicotinonitrile
- Example 5 The racemate from Example 5 was separated by chiral HPLC using CHIRALPAK IE (2*25 cm, 5 um) as the chiral stationary phase, a 2:1:1 (v/v/v) solution of ethanol:hexanes:dichloromethane as the mobile phase, and 10 mM ammonia in methanol as the additive.
- CHIRALPAK IE 2*25 cm, 5 um
- a 2:1:1 (v/v/v) solution of ethanol:hexanes:dichloromethane as the mobile phase
- 10 mM ammonia in methanol as the additive.
- CHO-K1 cells stably expressing human M 1 receptor with aequorin were grown in F12 media (Gibco) containing 10% FBS (ATCC), 0.4 mg/mL geneticin (Sigma-Aldrich) and 0.25 mg/mL Zeocin (Invitrogen). Cells were grown as per the manufacturer's protocol. For compound testing, cells were grown to confluency and detached gently with Accutase (Sigma-Aldrich) followed by centrifugation for 5 min at 150 ⁇ g. Cells were then re-suspended in assay buffer (i.e.
- DMEM/F-12 HEPES without phenol red (Invitrogen) with 0.1% BSA (Sigma-Aldrich) at a density of 5 ⁇ 10 6 cells/ml.
- BSA Sigma-Aldrich
- 5 ⁇ M coelenterazine (Invitrogen) was added to the cells, mixed, then incubated at room temperature protected from light, with gentle agitation, for 4 h.
- CHO-K1 cells stably expressing human M 2 , M 3 and M 4 receptors, respectively, with aequorin (Perkin Elmer) were used to assess a test compound's ability to dose-dependently reverse the EC 80 acetylcholine response.
- the IC 50 of the compounds was calculated from the dose response curve. Results for select compounds are shown in Table 2.
Abstract
Description
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
In some embodiments of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is
In some embodiments of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is
In some embodiments of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is
In some embodiments of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is
In some embodiments of a compound of Formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof, provided that the aforementioned combinations do not violate the rules of valency known to those skilled in the art.
p is 1, and R6 is selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy. In some embodiments, R3 is
p is 1, and R6 is selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy. In some embodiments, R6
p is 2, R6 is selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy. In some embodiments, R3 is
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3.
each R4 is independently selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C3-6 halocycloalkyl, C3-6 halocycloalkoxy, C1-6 alkylhydroxyl, or heterocycloalkyl;
R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 is independently selected from halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkoxy;
n is 1 or 2;
o is 0, 1, or 2; and
p is 0, 1, 2, or 3.
- ACN or MeCN acetonitrile
- aq aqueous
- Bn benzyl
- Bu butyl
- BOC or Boc tert-butyl carbamate
- BrettPhos 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′4′6′-triisopropyl-1,1′-biphenyl
- BSA bovine serum albumin
- CDI 1,1′-carbonyldiimidazole
- CHO Chinese hamster ovary
- Cy cyclohexyl
- dba dibenzylideneacetone
- DAST diethylaminosulfur trifluoride
- DCC N,N′-dicyclohexylcarbodiimide
- DCE dichloroethane (ClCH2CH2Cl)
- DCM dichloromethane (CH2Cl2)
- DIPEA or DIEA diisopropylethylamine
- DMAP 4-(N,N-dimethylamino)pyridine
- DME 1,2-dimethoxyethane
- DMF N,N-dimethylformamide
- DMA N,N-dimethylacetamide
- DMSO dimethylsulfoxide
- EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide
- equiv equivalent(s)
- Et ethyl
- EtOH ethanol
- EtOAc ethyl acetate
- FBS fetal bovine serum
- h hour(s)
- HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
- HOBT Hydroxybenzotriazole
- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- Hex hexanes
- HPLC high performance liquid chromatography
- LAH lithium aluminum hydride
- LCMS or LC-MS liquid chromatography-mass spectrometry
- LG leaving group
- M molar
- mCPBA meta-chloroperoxybenzoic acid
- Me methyl
- MeOH methanol
- min minute(s)
- MS mass spectroscopy
- NMM N-methylmorpholine
- NMP N-methyl-2-pyrrolidone
- NMR nuclear magnetic resonance
- Oxone Potassium peroxymonosulfate
- Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(O)
- Pd(PPh3)4 palladium tetrakistriphenyl phosphine
- Pd/C palladium on carbon
- PG protecting group
- PMB para-methoxybenzyl
- RT room temperature
- sec seconds
- T3P propylphosphonic anhydride
- TBAF tetrabutylammonium fluoride
- TEA triethylamine
- TFA trifluoroacetic acid
- THF tetrahydrofuran
- TLC thin layer chromatography
- XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Exam- | |||
ple | Structure | Name | [M + H]+ |
7 |
|
6-{3-[3-(3- fluorobenzenesulfonyl)propanoyl]- 3,8-diazabicyclo[3.2.1]octan-8- yl}pyridine-3-carbonitrile | 429.1 |
8 |
|
6-{3-[3-(3,5- difluorobenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 447.1 |
9 |
|
3-(3-methoxybenzenesulfonyl)-1- [8-(6-methylpyridazin-3-yl)-3,8- diazabicyclo[3.2.1]octan-3- yl]propan-1-one | 431.1 |
10 |
|
3-(3-methoxybenzenesulfonyl)-1- [8-(6-methylpyridin-3-yl)-3,8- diazabicyclo[3.2.1]octan-3- yl]propan-1-one | 430.1 |
11 |
|
6-{3-[3-(3-fluoro-5- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 459.1 |
12 |
|
6-{3-[3-(2- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 441.2 |
13 |
|
6-{3-[3-(5-fluoro-2- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 459.1 |
14 |
|
6-{3-[3-(3-fluoro-2- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 459.1 |
15 |
|
6-(3-{3-[(2-methoxypyridin-4- yl)sulfonyl]propanoyl}-3,8- diazabicyclo[3.2.1]octan-8- yl)pyridine-3-carbonitrile | 442.1 |
16 |
|
3-(3-methoxybenzenesulfonyl)-1- {8-[5-(trifluoromethyl)pyridin-2- yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}propan-1-one | 484.1 |
17 |
|
3-(3-methoxybenzenesulfonyl)-1- {8-[6-(trifluoromethyl)pyridazin- 3-yl]-3,8-diazabicyclo[3.2.1]octan- 3-yl}propan-1-one | 485.1 |
18 |
|
3-(3-methoxybenzenesulfonyl)- 1-[8-(5-methylpyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-3- yl]propan-1-one | 430.1 |
19 |
|
2-fluoro-5-{3-[3-(3- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}benzonitrile | 458.1 |
20 |
|
2-fluoro-4-{3-[3-(3- methoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}benzonitrile | 458.1 |
21 |
|
6-{3-[3-(3- cyclopropoxybenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine-3- carbonitrile | 467.2 |
22 |
|
6-{3-[3-(3- bromobenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 489.0, 491.0 |
23 |
|
6-(3-{3-[(3-cyclopropylpyridin- 2-yl)sulfonyl]propanoyl}-3,8- diazabicyclo[3.2.1]octan-8- yl)pyridine-3-carbonitrile | 452.1 |
24 |
|
6-{3-[3-(3-fluoro-2- methylbenzenesulfonyl) propanoyl]-3,8-diazabicyclo [3.2.1]octan-8-yl}pyridine- 3-carbonitrile | 443.1 |
25 |
|
6-(3-{3-[(2-cyclopropyl- pyridin-4-yl)sulfonyl] propanoyl}-3,8-diazabicyclo [3.2.1]octan-8-yl)pyridine- 3-carbonitrile | 452.2 |
26 |
|
6-(3-{3-[2- (difluoromethyl)benzene- sulfonyl]propanoyl}-3,8- diazabicyclo-[3.2.1]octan- 8-yl)pyridine-3-carbonitrile | 461.1 |
27 |
|
6-(3-{3-[(2-cyclopropylpyridin- 3-yl)sulfonyl]propanoyl}-3,8- diazabicyclo[3.2.1]octan-8- yl)pyridine-3-carbonitrile | 452.1 |
28 |
|
6-(3-(3-((2- bromophenyl)sulfonyl) propanoyl)-3,8-diazabicyclo [3.2.1]octan-8-yl)nicotinonitrile | 489.0, 491.0 |
29 |
|
6-(3-(3-((2- (trifluoromethyl)phenyl)sulfonyl) propanoyl)-3,8- diazabicyclo[3.2.1]octan-8- yl)nicotinonitrile | 479.1 |
30 |
|
6-(3-(3-((2- (trifluoromethoxy)phenyl) sulfonyl)propanoyl)-3,8- diazabicyclo-[3.2.1]octan- 8-yl)nicotinonitrile | 495.2 |
31 |
|
6-(3-(3-((2-(1,1- difluoroethyl)phenyl)sulfonyl) propanoyl)-3,8-diazabicyclo [3.2.1]octan-8-yl)nicotinonitrile | 475.1 |
32 |
|
6-(3-(3-((5-fluoro-2- methylphenyl)sulfonyl) propanoyl)-3,8-diazabicyclo [3.2.1]octan-8-yl)nicotinonitrile | 443.1 |
33 |
|
6-(3-(3-((3-fluoro-5- methylphenyl)sulfonyl) propanoyl)-3,8-diazabicyclo [3.2.1]octan-8-yl)nicotinonitrile | 443.1 |
34 |
|
6-(3-{3-[(3,5-dimethyl-1,2- oxazol-4-yl)sulfonyl]propanoyl}- 3,8-diazabicyclo[3.2.1]octan-8- yl)pyridine-3-carbonitrile | 430.2 |
TABLE 1 | |||
Example | M1 IC50 | ||
1 | A | ||
2 | B | ||
3 | A | ||
4 | A | ||
5 | B | ||
6 | D | ||
7 | B | ||
8 | B | ||
9 | C | ||
10 | D | ||
11 | B | ||
12 | B | ||
13 | B | ||
14 | B | ||
15 | B | ||
16 | C | ||
17 | C | ||
18 | D | ||
19 | C | ||
20 | B | ||
21 | C | ||
22 | C | ||
23 | C | ||
24 | A | ||
25 | C | ||
26 | C | ||
27 | B | ||
28 | C | ||
29 | C | ||
30 | C | ||
31 | C | ||
32 | C | ||
33 | C | ||
34 | |||
35 | A | ||
36 | C | ||
A = IC50 of less than 10 nM; | |||
B = IC50 less than 100 nM but greater than or equal to 10 nM; | |||
C = IC50 less than 1 μM (1,000 nM) but greater than or equal to 100 nM; | |||
D = IC50 less than 10 μM (10,000 nM) but greater than or equal to 1 μM (1,000 nM); | |||
E = IC50 greater than 1 μM (1,000 nM) |
TABLE 2 | |||||
Example | M2 IC50 | M3 IC50 | M4 IC50 | ||
2 | E | C | C | ||
3 | E | C | C | ||
24 | D | C | C | ||
35 | B | C | B | ||
A = IC50 of less than 10 nM; | |||||
B = IC50 less than 100 nM but greater than or equal to 10 nM; | |||||
C = IC50 less than 1 μM (1,000 nM) but greater than or equal to 100 nM; | |||||
D = IC50 less than 10 μM (10,000 nM) but greater than or equal to 1 μM (1,000 nM); | |||||
E = IC50 greater than 10 μM (10,000 nM) |
Claims (2)
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Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4803203A (en) | 1986-11-05 | 1989-02-07 | Warner-Lambert Company | Phenyl and heterocyclic piperazinyl alkoxy-benzheterocyclic compounds as antipsychotic agents |
US5089497A (en) | 1990-09-20 | 1992-02-18 | Warner-Lambert Company | Substituted piperazines as central nervous system agents |
WO1997023482A1 (en) | 1995-12-21 | 1997-07-03 | Pfizer Inc. | 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives |
WO2006010751A1 (en) | 2004-07-26 | 2006-02-02 | Applied Research Systems Ars Holding N.V. | N-hydroxyamide derivatives and use thereof |
US7071335B2 (en) | 2002-02-01 | 2006-07-04 | Euro-Celtique S.A. | 2-pyridinyl-1-piperazine therapeutic agents useful for treating pain |
US20070129378A1 (en) | 2005-12-01 | 2007-06-07 | Schering Corporation | Compounds for the treatment of inflammatory disorders and microbial diseases |
US20130178458A1 (en) | 2012-01-06 | 2013-07-11 | Vanderbilt University | Substituted (1-(methylsulfonyl)azetidin-3-yl)(heterocycloalkyl)methanone analogs as antagonists of muscarinic acetylcholine m1 receptors |
US8648074B2 (en) | 2011-09-29 | 2014-02-11 | Abbvie Inc. | Substituted octahydropyrrolo[1,2-a]pyrazine sulfonamides as calcium channel blockers |
US8999974B2 (en) | 2010-08-09 | 2015-04-07 | Raqualia Pharma Inc. | Acyl piperazine derivatives as TTX-S blockers |
WO2018089433A1 (en) | 2016-11-08 | 2018-05-17 | Navitor Pharmaceuticals, Inc. | PHENYL mTORC INHIBITORS AND USES THEREOF |
WO2019158572A1 (en) | 2018-02-15 | 2019-08-22 | Boehringer Ingelheim International Gmbh | Inhibitors of trpc6 |
WO2019212937A1 (en) | 2018-04-30 | 2019-11-07 | Ribon Therapeutics Inc. | Pyridazinones as parp7 inhibitors |
WO2019241131A1 (en) | 2018-06-11 | 2019-12-19 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
WO2020051153A1 (en) | 2018-09-04 | 2020-03-12 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
WO2021071843A1 (en) | 2019-10-07 | 2021-04-15 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
-
2020
- 2020-11-24 US US17/103,455 patent/US11752149B2/en active Active
-
2023
- 2023-07-25 US US18/225,992 patent/US20230364082A1/en active Pending
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4803203A (en) | 1986-11-05 | 1989-02-07 | Warner-Lambert Company | Phenyl and heterocyclic piperazinyl alkoxy-benzheterocyclic compounds as antipsychotic agents |
US5089497A (en) | 1990-09-20 | 1992-02-18 | Warner-Lambert Company | Substituted piperazines as central nervous system agents |
WO1997023482A1 (en) | 1995-12-21 | 1997-07-03 | Pfizer Inc. | 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives |
US7071335B2 (en) | 2002-02-01 | 2006-07-04 | Euro-Celtique S.A. | 2-pyridinyl-1-piperazine therapeutic agents useful for treating pain |
WO2006010751A1 (en) | 2004-07-26 | 2006-02-02 | Applied Research Systems Ars Holding N.V. | N-hydroxyamide derivatives and use thereof |
US20070129378A1 (en) | 2005-12-01 | 2007-06-07 | Schering Corporation | Compounds for the treatment of inflammatory disorders and microbial diseases |
US8999974B2 (en) | 2010-08-09 | 2015-04-07 | Raqualia Pharma Inc. | Acyl piperazine derivatives as TTX-S blockers |
US8648074B2 (en) | 2011-09-29 | 2014-02-11 | Abbvie Inc. | Substituted octahydropyrrolo[1,2-a]pyrazine sulfonamides as calcium channel blockers |
US20130178458A1 (en) | 2012-01-06 | 2013-07-11 | Vanderbilt University | Substituted (1-(methylsulfonyl)azetidin-3-yl)(heterocycloalkyl)methanone analogs as antagonists of muscarinic acetylcholine m1 receptors |
WO2018089433A1 (en) | 2016-11-08 | 2018-05-17 | Navitor Pharmaceuticals, Inc. | PHENYL mTORC INHIBITORS AND USES THEREOF |
WO2019158572A1 (en) | 2018-02-15 | 2019-08-22 | Boehringer Ingelheim International Gmbh | Inhibitors of trpc6 |
WO2019212937A1 (en) | 2018-04-30 | 2019-11-07 | Ribon Therapeutics Inc. | Pyridazinones as parp7 inhibitors |
WO2019241131A1 (en) | 2018-06-11 | 2019-12-19 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
US11512090B2 (en) | 2018-06-11 | 2022-11-29 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine M1 receptor antagonists |
WO2020051153A1 (en) | 2018-09-04 | 2020-03-12 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
US20210155629A1 (en) | 2018-09-04 | 2021-05-27 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
WO2021071843A1 (en) | 2019-10-07 | 2021-04-15 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
US20230089921A1 (en) | 2019-10-07 | 2023-03-23 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
Non-Patent Citations (17)
Title |
---|
Bender, A.M. et al. (Aug. 1, 2017, e-published May 15, 2017). "Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists," Bioorg Med Chem Lett 27(15):3576-3581. |
Extended European Search Report dated May 6, 2022, for EP Patent Application No. 19857624.1, 8 pages. |
International Search Report dated Dec. 29, 2020 for PCT Application No. PCT/US2020/054412, filed Oct. 6, 2020, 3 pages. |
International Search Report dated Nov. 21, 2019, for PCT Application No. PCT/US2019/049374, filed Sep. 3, 2019, 3 pages. |
International Search Report dated Oct. 18, 2019, for PCT Application No. PCT/US2019/036345, filed Jun. 10, 2019, 4 pages. |
Manetti, D. et al. (May 18, 2000). "Design, synthesis, and preliminary pharmacological evaluation of 1,4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents," Journal of Medicinal Chemistry 43(10):1969-1974. |
Melancon, B.J. et al. (Aug. 1, 2012, e-published Jun. 15, 2012). "Development of novel M1 antagonist scaffolds through the continued optimization of the MLPCN probe ML012," Bioorg Med Chem Lett 22(15):5035-5040. |
Melancon, B.J. et al. (Jan. 15, 2012, e-published Dec. 6, 2011). "Development of a more highly selective M1 antagonist from the continued optimization of the MLPCN Probe ML012," Bioorg Med Chem Lett 22(2):1044-1048. |
PubChem CID 101131894, (Create Date Dec. 17, 2015), located at <https://pubchem.ncbi.nlm.nih.gov/compound/101131894>, 7 pages. |
PubChem CID 101131895, (Create Date Dec. 17, 2015), located at <https://pubchem.ncbi.nlm.nih.gov/compound/101131895>, 8 pages. |
PubChem CID 102350371, (Create Date Dec. 25, 2015), located at <https://pubchem.ncbi.nlm.nih.gov/compound/102350371>, 7 pages. |
PubChem CID 70746046, (Create Date Mar. 4, 2013), located at <https://pubchem.ncbi.nlm.nih.gov/compound/70746046>, 5 pages. |
Sheffler, D.J. et al. (Aug. 2009, e-published Apr. 30, 2009). "A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning," Mol Pharmacol 76(2):356-368. |
Weaver, C. D. et al. (2009). "Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 orM1) antagonist in vitro and in vivo probe," Current Topics in Medicinal Chemistry 9(13): 1217-1226. |
Written Opinion dated Dec. 29, 2020 for PCT Application No. PCT/US2020/054412, filed Oct. 6, 2020, 3 pages. |
Written Opinion dated Nov. 21, 2019, for PCT Application No. PCT/US2019/049374, filed Sep. 3, 2019, 4 pages. |
Written Opinion dated Oct. 18, 2019, for PCT Application No. PCT/US2019/036345, filed Jun. 10, 2019, 6 pages. |
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